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BJA Advance Access originally published online on November 19, 2004
British Journal of Anaesthesia 2005 94(2):229-233; doi:10.1093/bja/aei029
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2004

Is the clinical efficacy of epidural diamorphine concentration-dependent when used as analgesia for labour?{dagger}

G. A. McLeod1,*, B. Munishankar1 and M. O. Columb2

1 Department of Anaesthetics, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. 2 Departments of Anaesthesia and Intensive Care Medicine, South Manchester University Hospital, Wythenshawe, UK

* Corresponding author. E-mail: g.a.mcleod{at}dundee.ac.uk

Accepted for publication October 5, 2004.


   Abstract
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 Footnotes
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Background. The physicochemical properties of diamorphine (3,6-diacetylmorphine) enhance its bioavailability compared with more lipid-soluble opioids when administered into the epidural space. However, the influence of concentration, volume or mass on the clinical efficacy of diamorphine is not known.

Method. In this double-blind, randomized, prospective study, 62 women in active labour and ≤5 cm cervical dilatation were recruited to determine whether the mode of action of diamorphine in the epidural space is concentration-dependent. After insertion of a lumbar epidural catheter, patients received epidural diamorphine 3 mg either as a high-volume, low-concentration solution (group A) or a low-volume, high-concentration solution (group B). The concentration of diamorphine was determined by the response of the previous patient in the same group using up–down sequential allocation. Pain corresponding to the previous contraction was assessed using a 100-mm visual analogue score and effective analgesia was defined as ≤10 mm within 30 min of epidural injection.

Results. There was no significant difference in EC50 for diamorphine between the groups: the difference was 15.0 µg ml–1 (95% CI –40.3 to 10.3). The EC50 for group A was 237.5 µg ml–1 (95% CI 221.2 to 253.8) and the EC50 for group B was 252.5 µg ml–1 (95% CI 232.2 to 272.8). The EC50 ratio was 0.95 (95% CI 0.87 to 1.06). The groups exhibited parallelism (P=0.98). The overall EC50 for all data was 244.2 µg ml–1 (95% CI 230.8 to 257.2).

Conclusion. We conclude that diamorphine provides analgesia in labour by a concentration-dependent effect.

Keywords: anaesthetic techniques, epidural; anaesthetic techniques, minimum dose; analgesics opioid, diamorphine


   Introduction
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 Footnotes
 Abstract
 Introduction
Methods
 Results
 Discussion
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Diamorphine (3,6-diacetylamorphine) is a semisynthetic opioid produced by the acetylation of morphine. It undergoes two rapid deacetylations, initially to the fat-soluble opioid 6-monoacetyl morphine, followed by a further 3-deacetylation to morphine after rapid entry into the central nervous system. These two active metabolites contribute to the analgesic effect of diamorphine.1

Diamorphine possesses many of the ideal physicochemical characteristics necessary for providing epidural pain relief in labour.1 Principally, it has an intermediate lipid solubility between fentanyl and morphine, enabling passage through both hydrophilic and hydrophobic tissues. Secondly, the free fraction of unionized drug with diamorphine is 11 times greater than that with fentanyl. Thirdly, diamorphine exhibits greater clearance from cerebrospinal fluid compared with morphine, thus reducing the potential for serious side-effects, such as respiratory depression.

Although epidural administration of diamorphine is widespread in the UK for pain relief after abdominal surgery2 and Caesarean section,3 its use in labour has been limited. Epidural administration of bupivacaine and diamorphine mixtures has provided good analgesia for labour as a bolus,4 5 infusion4 6 7 and combined spinal epidural.8 Only one published study has shown that diamorphine alone, albeit with a large (5 mg) dose,9 can provide pain relief in labour equivalent to a combination of diamorphine and bupivacaine. However, unlike local anaesthetics, for diamorphine the influence of volume, mass or concentration on the mode of action remains unknown.

Therefore, the aim of our study was to investigate the use of diamorphine for analgesia in labour using the method of sequential allocation to determine whether the mode of action is concentration-dependent and, if so, to determine its median effective concentration (EC50) and concentration–response curve.


   Methods
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 Footnotes
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Sixty-two patients were recruited to this randomized double-blind study after approval by the local medical ethics committee and informed patient consent. Only women in active labour between 2 and 5 cm dilatation, ≥37 weeks gestation and who had not received opioids within the previous 12 h were recruited. Only patients in early labour with mild contractions or patients admitted electively to the labour ward before induction of labour were approached in order to discuss the study and gain written consent. Patients in active labour, with moderate or severe pain, were not approached for recruitment into this study. Other exclusions included patients ≤37 weeks gestation, maternal medical or obstetric illness and any evidence of fetal distress or poor fetal growth.

After starting an i.v. crystalloid infusion, and with the patient in the left lateral position, a Touhy needle was inserted at the L 2/3 interspace using loss of resistance to saline and a catheter inserted 3 cm into the epidural space. Saline injection was minimized to <2 ml to avoid dilution of opioid solutions. All epidurals were inserted by a single investigator (B.M.), blinded to the patient group, whose standard technique is to insert epidural catheters caudally at L 2/3. Data from our yearly obstetric anaesthesia audit has regularly shown that caudal epidural catheters, inserted by B.M., have consistently provided good pain relief. Patients were randomized into two groups. All patients received a fixed dose of 3 mg diamorphine. The first group (A) received a high-volume, low-concentration injection starting at 20 ml diamorphine 150 µg ml–1 and the second group (B) received a low-volume, high-concentration epidural injection starting at diamorphine 600 µg ml–1, 5 ml. No test dose was given and time zero was designated as the time at which the epidural injection was completed.

Pain scoring was conducted by trained midwives, as pain scoring is mandatory for all epidurals in our unit. Pain corresponding to the peak pain associated with the previous contraction was measured every 5 min by the patient with a visual analogue scale (VAS), whereby 0 mm corresponded to no pain and 100 mm to the worst pain imaginable.

Three outcomes resulted from VAS scoring and dictated the concentration of drug given to the next patient, based on a dosing interval of 25 µg ml–1. This is termed sequential allocation.

Effective: VAS score ≤10 mm at any time during the study period. The next patient was given 25 µg ml–1 less diamorphine.

Ineffective: VAS score >10 mm at all times during the study period but pain resolved after a bolus of bupivacaine 0.25%, 10 ml. The next patient was given 25 µg ml–1 more diamorphine.

Exclude: VAS score >10 mm at all times during the study period but pain did not resolve after a bolus of bupivacaine 0.25%, 10 ml. After an exclusion, the next patient was allocated to the same group and same concentration of solution.

After the study, pain relief was maintained throughout labour with patient-controlled epidural boluses of bupivacaine 0.1% w/v, 15 ml. Hourly monitoring of maternal heart rate, non-invasive arterial pressure, respiratory rate, itching and nausea and vomiting was undertaken until 2 h after delivery. In addition, mode of delivery was noted and fetal welfare was assessed using continuous cardiotocogram, Apgar scores and umbilical arterial and venous pH.

Statistical analysis
Data are presented as mean (SD) and count and were analysed using Student's t test and Fisher's exact test as appropriate. Median effective concentrations with 95% confidence intervals (CI) were estimated from the sequences using the up–down method of Dixon and Massey. The responses at each dose level were also analysed using probit regression to estimate EC50.10 Analyses were carried out using the following software: Microsoft Excel 2000 (Microsoft, Redmond, WA, USA) and Number Cruncher Statistical Systems (NCSS 2001, Kaysville, UT, USA). Bioequivalence was concluded if the 95% confidence interval of the ratio of EC50 was contained within the 0.8 to 1.25 limits. Statistical significance was defined for an overall {alpha} error at the 0.05 level and P values were two-sided.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Sixty-two patients were recruited to this study. There were two exclusions because of protocol violation. There were no differences between the groups in patient characteristics or obstetric details (Table 1). Maternal and fetal outcomes were similar in the two groups (Table 2) and the incidence of side-effects was low (Table 1). No patient had a measured respiratory rate <12 bpm at any time during or after labour. Pain relief was consistently provided in all patients in group B receiving at least diamorphine 300 µg ml–1. The concentration at which oscillation occurred was similar in the two groups of patients. The EC50 for group A was 237.5 µg ml–1 (95% CI 221.2 to 253.8 µg ml–1) using the Dixon and Massey method and 239.1 µg ml–1 (95% CI 224.3 to 255.1 µg ml–1) using probit regression (Fig. 1). The EC50 for group B (Fig. 2) was 252.5 µg ml–1 (95% CI 232.2 to 272.8 µg ml–1) using the Dixon and Massey method and 251.4 µg ml–1 (95% CI 232.0 to 269.1 µg ml–1) using probit regression. The difference between groups was 15.0 µg ml–1 (95% CI –40.3 to 10.3 µg ml–1). The EC50 ratio was 0.95 (95% CI 0.87 to 1.06) and the 95% CI was contained within the bioequivalence (0.8–1.25) limits. The concentration–response relationships exhibited parallelism (P=0.98). Bioequivalence was therefore concluded and the data were combined to give the overall EC50 as 244.2 µg ml–1 (95% CI 230.8 to 257.2 µg ml–1) using probit analysis. The concentration–response relationship is shown in Figure 3.


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  		Table 1 Patient characteristics, obstetric data and side-effects

 

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  		Table 2 Duration of first and second stages of labour, mode of delivery and fetal outcomes

 


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  		Fig 1 Patient sequence and diamorphine concentration for patients in group A: low concentration, high volume. Filled symbols, successful analgesia; open symbols, unsuccessful analgesia.

 


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  		Fig 2 Patient sequence and diamorphine concentration for patients in group B: high concentration, low volume. Filled symbols, successful analgesia; open symbols, unsuccessful analgesia.

 


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  		Fig 3 Logit concentration–response plot.

 

   Discussion
Top
 Footnotes
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study has shown, using a well-established method,11 that the concentration of diamorphine at which oscillation occurred was similar in the two groups of patients, indicating that the mode of action of epidural diamorphine is concentration-dependent when administered for pain relief in early labour. The two groups can be regarded as equivalent as the 95% CI of the EC50 ratio is contained within acceptable limits for bioequivalence (0.80–1.25) and the slopes of the derived dose–response curves were parallel.

This study also confirms the results of previous research,9 that diamorphine alone can provide good pain relief in labour. All patients receiving more than diamorphine 300 µg ml–1 experienced good pain relief in labour of an intensity comparable to that of local anaesthetics in other studies (VAS pain score ≤10 mm).10–12 In contrast, patients receiving high-volume, low-concentration diamorphine, starting at a volume of 20 ml and concentration of 150 µg ml–1, had a variable response and oscillation occurred at a median concentration of 237.5 µg ml–1.

We consider it important, in studies of analgesics substituting for local anaesthetics in early labour, that the standard of pain relief should be equivalent to that deemed acceptable with local anaesthetics. Therefore, we defined good pain relief as a VAS score ≤10 mm within 30 min of epidural injection.

Unlike local anaesthetics, epidural diamorphine has not hitherto been studied with respect to the influence of volume, mass or concentration on the clinical efficacy. Several studies have shown that the mode of action of lidocaine,11 bupivacaine,11 levobupivacaine12 and ropivacaine13 is concentration-dependent. The evidence of high-quality pain relief in labour with diamorphine,9 of a magnitude similar to that of the local anaesthetics mentioned above, allowed us to use the method of sequential allocation, used routinely to measure the EC50 of local anaesthetics, in order to estimate the EC50 of diamorphine. Although the EC95 may be regarded as clinically useful, we regard the EC50 as a more sensitive means of comparing drug concentrations as the EC50 represents the point of maximal slope of the cumulative concentration–response curve.

We have shown that, like local anaesthetics, diamorphine has a mode of action that is dependent on concentration, but that the volume of diamorphine associated with good clinical efficacy differs from that of local anaesthetics. Small, highly concentrated, volumes of diamorphine provided good pain relief in early labour in this study, whereas local anaesthetics have been shown to require a large volume to fill the discontinuous and segmented14 lumbar epidural space and spread out through the intervertebral foraminae15 in order to block nerve roots.

Provision of good pain relief by high-concentration, low-volume solutions of epidural diamorphine may be attributed to its site of action—opioid receptors within the grey matter of the spinal cord. Bioavailability of diamorphine to the opioid receptors is a balance between the pharmacological properties of the drug (Table 3) and the relative lipid/water solubility and the vascularity of the tissues through which it passes. The intermediate lipid solubility of diamorphine, as indicated by an octanol–water distribution coefficient of 280, lends itself to traversing both hydrophobic and hydrophilic tissue compartments, thus increasing permeability when compared with either morphine or fentanyl.16 17 Furthermore, diamorphine's lower protein binding and lower pKa (and hence lower ionization)18 compared with fentanyl increases bioavailability onto opioid receptors within the spinal cord.


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  		Table 3 Physicochemical characteristics of diamorphine, fentanyl and morphine1 18

 
No differences in obstetric or fetal outcomes existed between groups. The durations of the first and second stages of labour, mode of delivery and the condition of all newborn infants, as determined by Apgar scores and umbilical pH, were all comparable with those in a previous local anaesthetic study in our unit.19 The incidence of side-effects in our study is less than in another study in which epidural diamorphine 3 mg was given by bolus.4 In our study, only one-quarter of the patients experienced nausea and vomiting, 23% had sedation scores of ≥1 and respiratory rates were maintained >12 bpm at all times. In contrast, in a study4 measuring the efficacy and side-effects of diamorphine bolus and infusion, a 10 ml bolus of epidural diamorphine 3 mg mixed with bupivacaine 0.25% was associated with nausea in 63% of patients and sedation score ≥1 in 100% of patients. Epidural infusions of diamorphine have been associated with a smaller incidence of side-effects. Using an infusion of diamorphine 300 µg h–1 and bupivacaine 0.1% at a rate of 10 ml h–1, Daniel and McGrady4 significantly reduced the incidence of nausea and vomiting to 33% whereas Hill and colleagues,6 in a dose-finding study, described an incidence of nausea and vomiting of 13% when diamorphine was infused at 400 µg h–1 and 40% when diamorphine was infused at 533 µg h–1. The former study hypothesized that the low incidence of side-effects with diamorphine infusions was suggestive of a lower systemic effect of diamorphine and, by inference, a greater local spinal cord effect.

This study, however, was not designed to answer whether the efficacy of epidural diamorphine is by direct binding to opioid receptors at spinal cord level or by systemic redistribution via subdural blood vessels20 and block of opioid receptors within the spinal cord and brain. A previous study9 suggests that both mechanisms may be pertinent; the concomitant use of epidural epinephrine with diamorphine reduced plasma concentrations of morphine, suggesting that the mode of action of diamorphine is partly systemic. Further studies are necessary to determine whether high-concentration, low-volume diamorphine passing down a steep concentration gradient is associated with less side-effects, lower systemic blood levels and longer duration of action due to a predominantly spinal action.

The clinical advantage of such an epidural solution would be the provision of early pain relief in labour without motor block, thus allowing ambulation. Although the combined spinal epidural technique is popular for initiating pain relief and providing ambulation, many anaesthetists remain reluctant to breach the dura mater in early labour and, instead, provide pain relief with low-concentration, high-volume mixtures of epidural local anaesthetic and fentanyl.

However, before embarking on randomized, controlled outcome studies of the efficacy and side-effects of epidural diamorphine, we are first using the method of sequential allocation to determine whether the addition of local anaesthetics to diamorphine confers any synergistic benefit, and whether epidural diamorphine exhibits any volume dependence.

In conclusion, we have shown that diamorphine provides effective analgesia in early labour and that this effect is concentration-dependent.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
{dagger} This work was presented by Dr G. A. McLeod to the Anaesthetic Research Society, Aberdeen, 2004. Back


   References
Top
 Footnotes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Kaufman L. Intraspinal diamorphine: epidural and intrathecal. In: Scott DB, ed. Diamorphine. Cambridge: Woodhead-Faulkner Limited, 1988

2 Carson D, Binning A, Thomson M. Epidural analgesia in Scotland: a survey of extradural opioid practice. Health Bull (Edinb) 1996; 54: 51–62

3 Hallworth SP, Fernando R, Bell R, Parry MG, Lim GH. Comparison of intrathecal and epidural diamorphine for elective Caesarean section using a combined spinal-epidural technique. Br J Anaesth 1999; 82: 228–32[Abstract/Free Full Text]

4 Daniel M, McGrady EM. Epidural diamorphine. A comparison of bolus and infusion administration in labour. Anaesthesia 1995; 50: 14–6[Web of Science][Medline]

5 McGrady EM, Brownhill DK, Davis AG. Epidural diamorphine and bupivacaine in labour. Anaesthesia 1989; 44: 400–3[Web of Science][Medline]

6 Hill DA, McCarthy G, Bali IM. Epidural infusion of alfentanil or diamorphine with bupivacaine in labour—a dose finding study. Anaesthesia 1995; 50: 415–9[Web of Science][Medline]

7 Lowson SM, Eggers KA, Warwick JP, Moore WJ, Thomas TA. Epidural infusions of bupivacaine and diamorphine in labour. Anaesthesia 1995; 50: 420–2[Web of Science][Medline]

8 Vaughan DJ, Ahmad N, Lillywhite NK, Lewis N, Thomas D, Robinson PN. Choice of opioid for initiation of combined spinal epidural analgesia in labour—fentanyl or diamorphine. Br J Anaesth 2001; 86: 567–9[Abstract/Free Full Text]

9 Keenan GM, Munishankarappa S, Elphinstone ME, Milne MK. Extradural diamorphine with adrenaline in labour: comparison with diamorphine and bupivacaine. Br J Anaesth 1991; 66: 242–6[Abstract/Free Full Text]

10 Dixon WJ, Massey FJ. Introduction to Statistical Analysis, 4th edn. New York: McGraw-Hill, 1983; 428–39

11 Columb MO, Lyons G. Determination of the minimum local analgesic concentrations of epidural bupivacaine and lidocaine in labour. Anesth Analg 1995; 81: 833–7[Abstract]

12 Lyons G, Columb M, Wilson RC, Johnson RV. Epidural pain relief in labour: potencies of levobupivacaine and racemic bupivacaine. Br J Anaesth 1998; 81: 899–901[Abstract/Free Full Text]

13 Polley LS, Columb MO, Naughton NN, Wagner DS, van de Ven CJ. Relative analgesic potencies of ropivacaine and bupivacaine for epidural analgesia in labor: implications for therapeutic indexes. Anesthesiology 1999; 90: 944–50[CrossRef][Web of Science][Medline]

14 Hogan Q, Toth J. Anatomy of soft tissues of the spinal canal. Reg Anesth Pain Med 1999; 24: 303–10[CrossRef][Web of Science][Medline]

15 Hogan Q. Epidural catheter tip position and distribution of injectate evaluated by computed tomography. Anesthesiology 1999; 90: 964–70[CrossRef][Web of Science][Medline]

16 Bernards CM. Understanding the physiology and pharmacology of epidural and intrathecal opioids. Best Pract Res Clin Anaesthesiol 2002; 16: 489–95[Medline]

17 Bernards C, Hill H. Physical and chemical properties of drug molecules governing their diffusion through the spinal meninges. Anaesthesiology 1992; 77: 750–6[CrossRef][Web of Science][Medline]

18 Camu F, Vanlersberghe C. Pharmacology of systemic analgesics. Best Pract Res Clin Anaesthesiol 2002; 16: 475–88[Medline]

19 Burke D, Henderson DJ, Simpson AM, et al. Comparison of 0.25% S(–)-bupivacaine with 0.25% RS-bupivacaine for epidural analgesia in labour. Br J Anaesth 1999; 83: 750–5[Abstract/Free Full Text]

20 Kozody R, Palahniuk RJ, Wade JG, Cumming MO, Pucci WR. The effect of subarachnoid epinephrine and phenylephrine on spinal cord blood flow. Can Anaesthesiol Soc J 1984; 31: 503–8


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G. A. McLeod, B. Munishankar, and M. O. Columb
An isobolographic analysis of diamorphine and levobupivacaine for epidural analgesia in early labour
Br. J. Anaesth., April 1, 2007; 98(4): 497 - 502.
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